In this session, Dr Antonio Urbano Carrillo, PhD, Geneticist at UR Vistahermosa, Alicante, Spain talked about genetic carrier screening, types of carrier screening panels available, reasons for testing and how it works.
The Genetic Carrier Screening has one objective, which is to identify “high genetic risk” couples, based on the carrier status of the members of the couple. Its last objective is to plan correctly the pregnancy of this couple.
Dr Carrillo further explains how the Mendelian disease is transmitted. The human being has two alleles for every gene, and for a better understanding, one is inherited from the father, and one is inherited from the mother.
About the Mendelian disease, Dr Carrillo can distinguish at least 3 types:
1. Autosomal Dominant.
This disease is characterized because the patient has pathogenic in one or two alleles, which is enough to cause the disease. So, the carrier of this pathogenic variant will develop this disease.
The transmission of the pathogenic alleles occurs in 50% of cases, so half of the patients’ offspring may be made of females and will inherit and develop the disease too. For example, Huntington’s Chorea or Marfan Syndrome.
These diseases are the focus of the genetic carrier screening because, usually, patients already know their carrier status.
2. Autosomal Recessive.
Variants can occur in both copies of the gene. The pairing of an individual with an autosomal recessive condition is carrying one copy of a mutated gene, but the typical does not show signs or symptoms of the condition. They’re silent carriers of the disease.
This disorder is typically not seen in every generation of an affected family. Moreover, the offspring have a 25%, and one of four members of the offspring is at risk of inhering this disease.
3. X-Linked Recessive.
Sons who inherit the pathogenic variant will be affected, while daughters are heterozygous, and usually asymptomatic carriers.
However, for males with existing diseases, all the daughters will be heterozygous for this condition, and all or some of the sons will be healthy.
Dr Carrillo shows a data where it demonstrates the importance of genetics, such as:
According to Dr Carrillo, if they pass a commercial filter to this data, they obtain the following:
According to Carrillo, they must search for the core disease to offer couples a balance between genetic security, price, and time and, above all, using the common cells.
Nowadays, it’s possible to sequence almost all genes in the genome, but it doesn’t make sense to do so, at least now, because it’s expensive and time-consuming.
Moreover, Dr Carrillo considers this topic something difficult to answer because they may not have the correct answer. It’s important to follow the International Society Guidelines and use the experience of each laboratory in the realization of this kind of analysis or test.
These are some of the most important international societies that each have their recommendations on which diseases should be included in the carrier screening.
Some recommendations to know which diseases to include are:
Carrillo mentions that these recommendations are for the diseases that must be included, but they also need some recommendations for what variants of the gene they must include because they have to include, in the carrier screening, the following:
There are also some recommendations to exclude some diseases from the screening, such as:
Even if it seems otherwise, more is not always better. The most important criteria are stability and prevalence of the disease. Since all these 70 diseases with high prevalence in the population will be included, but in case of prevalence, is considered high, and therefore, its threshold.
The study by Dr Muzzey shows the number of disease that meet the two criteria: severity and prevalence. This is demonstrated in the graphic when you can observe that if the threshold of 1 in 100, there are 18 conditions that 84% of risk couples can be detected.
However, if the threshold is lowered to 1 in 500, there are 91 conditions, and they can detect about 95% of a risk couple. Therefore, this could be adjusted to the needs of most couples.
Another factor important to consider is, depending on the number of genes included in the study, they will increase the probability of finding pathogenic variants in the patients.
As shown in the table, if they study 549 genes, the probability of the patient having at least one pathogenic variant is 84%. If they study 200 genes, the probability is 56%, while in the study of 15 genes, the probability is around 10-20% of pathogenic variants in patients. These are the same genes previously seen in Dr Muzzey’s study. All of these genes have a prevalence of less than 1 in 100.
As it can be seen in the market of the genetic carrier screen, there is a great variability in the number of genes that are included in the different studies. Of all these panels, 89% are coinciding in all of them, which considerately are the same to those seen, 91 genes from the study of Dr Muzzey.
Some examples of panels are the following:
This is the little one. There are 38 genes divided into two:
This panel is used with the Whole Exome Technology.
There are around 552 genes included, and it’s compatible with all panels on the market.
As seen before, a genetic carrier screening provider must include 89 genes, but 850 genes don’t match. This can be a problem for a couple who have performed this test at two different sites, as they may be carriers of pathogenic variants in genes that aren’t included in the panel performed. For instance, a member of a couple may be a carrier of a pathogenic variant in a gene that’s not included in the other test that the partner has done.
This can be solved with the Whole Exome Technology, so they would have the information of almost all of the existing genes. At Dr Carrillo’s center, they use this technology as a guarantee of compatibility of the existing panels in the market.
Dr Carrillo then shows an informative table with the genetic diseases included in the basic panel as well as the prevalence of carriers in Caucasian or European people.
Some of the genetic diseases are:
Furthermore, there are more genetic diseases included in the extended panel related to X-linked genes.
In this table, you can find:
About the basic panel, Carrillo mentions that they add a small number of genes using a closed panel. This is a targeted panel, meaning is closed, which allows to reduce costs, but they don’t have the flexibility that they have with the expanded panel.
They have a recommendation that in their laboratory to use the full exam sequencing technology for a matter of compatibility with other tests. Thanks to the Whole Exome Sequence, they can reduce the residual risk.
In addition, the pseudo-risk is a risk that remains after a negative result in the test performed. This residual risk is much lower when a complete sequencing of the gene is done, not studied and aimed at 13 mutations. This may suppose risk to be taken into account, especially in diseases with a high carrier rate, but which don’t have a well-defined pathogenic variant.
Moreover, they also must take into consideration the limitation of MDS, the technology used for this panel in the complementary studies where they do:
For a complete study of the couple, a fundamental test to perform is the karyotype, which allows to detection of chromosomal anomalies in couples as they normally go silent until the reproduction, and it can lead to repeated miscarriages or implanted failures.
It’s highly recommended, I would say almost mandatory, the realization of the karyotype, in addition to the screening of the genetic carrier screening before the start of the assisted reproduction cycle. – advises Dr Carrillo.
Dr Carrillo mentions that the best time to do an expanded genetic carrier screening is before starting the assisted reproduction cycle.
They can do it sequentially, first in one member of the couple and then the other, or simultaneously.
If it’s done sequentially:
Genetic matching is to make sure that the couple don’t share pathogenic variants in the same genes. This concept is particularly interesting in the gamete donation because the couple gets the greatest genetic security specialists can offer.
However, unfortunately, the risk today is never zero. We can reduce it, but we can never go to zero.- states Dr Carrillo.
This is a scan showing the possibilities that Dr Carrillo can find when doing the sequential study.
First, they study women, including the X-linked genes. If there’s no pathogenic mutation, they can continue with the cycle. However, if they detect a pathogenic mutation, they need to study the male.
If the male has no mutation in the same gene, they’re considered a low-risk couple and they can continue with the cycle.
If the couple share the mutation in the same gene, they’re considered a high-risk couple. It should be noted that if the couple is of high-risk, there are some solutions that can be offered to have a healthy offspring, such as PGT-M or gamete donation.
Dr Carrillo shows the management of a couple who performed a cycle of gamete donation.
Both the patient and the donor perform the same test or a compatibility test, thanks to the Whole Exome Technology.
If the patient and the donor share the pathogenic variant in the same gene, it’s considered a high-risk couple, so the donor must be changed. So, they look for a donor compatible with the couple.
If the female donor has an X-linked gene or pathogenic variant, the donor is discarded as she cannot donate her gametes.
In conclusion, Dr Carrillo talks about some of the key points of his presentation:
This carrier screening isn’t aimed at mitochondrial disease, and it’s not aimed at a person with a family history. This is for patients who don’t have any familiar history. Genetic carrier screening is used for patients who do not carry diseases and screen for the general risk of being the carrier of those diseases. It’s not a specific study, it’s a general study to reduce risks. For the mitochondrial disease, we have to see what we can do with a panel specific for mitochondrial disease. If the patient has a family history, we do genetic counselling, and we can study this specific disease condition.
I think that is recommended and mandatory because there are diseases that people of 25, and 21, are carriers of these diseases. This is a tool we can use to facilitate the final objective, which is to have a healthy baby in your home when you start a reproduction cycle. This is the only to give them genetic security. Genetic security isn’t the best term, but this is the closest term that we can use. I think it’s very, very recommendable to do this carrier screening for at least the 15 most prevalent diseases.
The expanded panel is more complicated to suggest. We can see in marketing, websites, and on the Internet, some providers have 1,000 genes. If we follow the International Society’s recommendations, we don’t have to do so many genes because, in 1,000 genes, you have genes that don’t fulfil the recommendations of the International Society. For example, when there are non-severe diseases that have been demonstrated that shouldn’t be included, like Alpha-1 antitrypsin, which is included in some panels, the International Society said that you don’t have to include this disease because if you have two pathogenic variants of this gene, this doesn’t mean you will have an illness, so you can be a carrier but not be ill. In that case, we would generate a problem and not the solution for the situation because we can’t predict the phenotype if the child will be ill or healthy.
PGT-A is a technique that almost all laboratories use the same technology. A few years ago, we could use an array of CGH. Nowadays, all the laboratories use NGS. You must do the PGT-A with NGS because it’s the only technology that permits you to detect 20% of mosaicism, it’s the critical topic in the PGT-A, and nowadays, this is the most successful. Only NGS have the potential to detect this 20-30% of mosaicism of every embryo.
What happens if, for example, a patient learns that he has some carrier disease, is he a carrier of genetic diseases, and how does it work? Does he have a consultation?
Here at UR Vistahermosa we have our own geneticist from the group. We have a genetic unit and the patient has a consultation, for international patients we usually do a video consultation with the geneticist, where they are given the options that we have to help them out with their problem.
